The protease-antiprotease hypothesis of emphysema pathogenesis has support from many human[unreadable] and animal studies. A longstanding tenet of this hypothesis has been that proteases relevant to[unreadable] emphysema pathogenesis must be capable of degrading elastin. However, data in recent years[unreadable] indicates that collagenolytic activity may induce emphysema. Membrane-type 1 matrix[unreadable] metalloproteinase (MT1-MMP), a cell-surface MMP that cleaves fibrillar collagens, and EMMPRIN, an[unreadable] inducer of MT1-MMP, are detectable in emphysematous lung tissue, suggesting a role for MT1-MMP in[unreadable] emphysema pathogenesis. Moreover, monocyte migration in vitro requires MT1-MMP so that MT1-[unreadable] MMP is likely to be involved in the accumulation of macrophages in the lungs from smoking as well as[unreadable] in destruction of alveolar walls. The studies we propose will determine the roles of MT1-MMP and[unreadable] EMMPRIN in the pathogenesis of emphysema. We will determine whether levels of MT1-MMP and[unreadable] EMMPRIN expression by monocytes, at baseline and upon stimulation, have a relationship to[unreadable] monocyte migration among smokers with and without emphysema, and whether levels of MT1-MMP[unreadable] and EMMPRIN expression by alveolar macrophages correlate with emphysema as determined by chest[unreadable] computed tomography (CT). To accomplish these objectives we will assess the role of MT1-MMP on[unreadable] the migration of smokers' monocytes with MT1-MMP blocking antibodies, and we will measure MT1-[unreadable] MMP and EMMPRIN mRNAs by quantitative PCR on alveolar macrophages harvested by[unreadable] bronchoalveolar lavage and laser capture microdissection. These studies will be complemented by[unreadable] analyses of the pulmonary responses to tobacco smoke in mice with targeted deletions ("knockouts") of[unreadable] the genes for MT1-MMP or EMMPRIN, and in mice with deletion of the gene for TIMP-2, the principal[unreadable] inhibitor of MT1-MMP. Taken together, the proposed studies will contribute new understanding of[unreadable] mechanisms of pulmonary inflammation and emphysema that occur in response to tobacco smoke.[unreadable]